Drosophila melanogaster is a powerful model organism for understanding the genetic, molecular and neural bases of animal behaviors. Circadian rhythms are a prime example of behaviors whose molecular and neural foundations have been greatly increased by studies in Drosophila. A biological clock dictates that animals sleep and wake with a ca. 24-hour period, and this is true even when they are kept under constant conditions, without any information from the environment. Using genetic screens, many essential clock proteins (e.g. PER, TIM, figure 1) were identified in Drosophila. It has been shown that homologues of most of these proteins are also involved in generating mammalian circadian rhythms. Human homologues of Drosophila PER (hPER2) and DBT (hCK-Id) are actually mutated in patients with advanced sleep-phase syndrome. This demonstrates that the discoveries made in Drosophila are playing a crucial role in understanding human circadian behavior.

The Drosophila circadian pacemaker is a transcriptional feedback loop (fig.1), in which PER and TIM negatively regulate their own transcription. Kinases and phosphatases determine the pace of this feedback loop by controlling PER and TIM phosphorylation, and hence their stability and repressive activity. Recent studies, including work from our lab, show that at least in circadian pacemaker neurons (the small ventral lateral neurons, fig.2) translational control of the key pacemaker protein PER is also critical for 24-hour period behavioral rhythms. Ataxin-2 - whose mammalian homolog is involved in various neurodegenerative diseases – promotes PER translation with the help of the translational factor TYF. A major objective of our lab is thus to understand the mechanisms by which Ataxin-2, and more generally RNA binding proteins, control circadian rhythms.

The other major goal of our lab is to discover the mechanisms by which circadian rhythms are synchronized with the day/night cycle. These mechanisms are critical, since the period of circadian rhythms only approximates 24 hours, and day length changes at most latitudes over the course of the year. We are thus elucidating the cell-autonomous molecular mechanisms by which light and temperature inputs synchronize circadian molecular pacemakers. Interestingly, it has recently become clear that communication between circadian neurons is also critical to properly synchronize circadian behavior. Therefore, we also study the circadian neurons that detect light and temperature inputs, and determine how these neurons communicate with the rest of the circadian neural network. Our ultimate goal is to understand how different environmental inputs are integrated to optimize daily animal physiology and behavior.

Figures

Fig.1: The circadian pacemaker is a transcriptional feedback loop. It is synchronized with light by the intracellular photoreceptor CRY, which binds to TIM and triggers its proteasome degradation, mediated by JET.

Potential Rotation Projects

Circadian clocks play an essential role in the temporal organization of animal physiology and behavior.Proper synchronization of these clocks with the day/night cycle is essential for their function. We combine the powerful genetics of Drosophila with molecular, cell culture and behavioral approaches to obtain a comprehensive view of the mechanisms regulating circadian rhythms and their synchronization.

Rotation projects could for example focus on the mechanisms of signal transduction in the CRY light input pathway, on the molecular mechanisms underlying circadian temperature responses, or on characterizing the neural network controlling the synchronization of circadian behavior with light and temperature cycles.

Post Docs

A postdoc position is available to study circadian rhythms in Drosophila. Contact Patrick Emery (patrick.emery@umassmed.edu).

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